Project Summary/Abstract White matter plays a critical role in brain communication and connectivity. While schizophrenia has been hypothesized to be a dis-connection syndrome, the exact biological nature of white matter abnormalities in this disease is still unknown. Furthermore, while multiple publications report white matter abnormalities in schizophrenia, those findings to date have not lead to further understanding of schizophrenia etiology or new developments in pharmacological treatment. This is primarily because imaging measures remain nonspecific to the underlying microstructural pathology, and changes observed with MRI have been viewed as an ongoing consequence of gray matter pathological processes, thus not worth pursuing the possibility of white matter involvement further. In this application we propose to go beyond measuring white matter integrity. We hypothesize that white matter in schizophrenia may be compromised by several, distinct pathological processes that can be observed at different stages of the disease (some even before the presence of clinical symptoms), and thus could potentially constitute biomarkers of risk, onset, and outcome of schizophrenia. The overall goal of this proposal is to use Diffusion MRI, along with the newest MRI acquisition and analysis methods, and to apply them to distinct schizophrenia and schizophrenia related populations (both retrospectively as well as prospectively). With these tools and measures, we intend to test three related, complementary theories: A) Schizophrenics as well as subjects at risk for developing schizophrenia share white matter signatures that may be related to neurodevelopmental disruptions of white matter geometry; B) acute psychosis is likely associated with a pathology (neuroinflammation) affecting the extracellular volume; and C) chronic schizophrenia is likely associated with increasing cellular (myelin) pathology. The assembled team of computer scientists and clinical neuroscience researchers will work to localize and to characterize the neurobiology that underlies white matter changes which are frequently reported along the time course of schizophrenia. The results of this study will have an important impact on our understanding of mechanisms underlying schizophrenia, and provide imaging biomarkers of vulnerability, psychosis, outcome, and measures that can be used to monitor the efficacy of medical treatment. What makes this application unique is the assembly of tools that go beyond standard DTI, and access a number of schizophrenia populations, where these tools can be all applied.